JPWO2018030317A1 - Usage and dose of therapeutic agent for endometriosis - Google Patents

Abstract

An object of the present invention is to provide a drug that reduces the risk of bone mineral loss based on the estrogen-lowering effect and exhibits excellent therapeutic effect on endometriosis. The present invention relates to 3- [2-fluoro-5- (2, 3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [ A pharmaceutical composition for treating endometriosis, which comprises 3,4-d] pyrimidine-5-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the free compound has a value of 50 mg to 75 mg of the compound. Is orally administered once daily as a daily dose.

Description

  The present invention relates to a drug that reduces the risk of lowering bone mineral density based on the estrogen-lowering effect, and exerts an excellent therapeutic effect on endometriosis.

  More specifically, 3- [2-fluoro-5- (2, 3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [ A pharmaceutical composition for treating endometriosis, which comprises 3,4-d] pyrimidine-5-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the free compound has a value of 50 mg to 75 mg of the compound. Is orally administered once daily as a daily dose.

  Endometriosis is a disease in which the endometrium or similar tissue develops at sites other than the uterus depending on the increase in estrogen. Endometriosis is a benign disease but causes pain such as menstrual pain and decreased fertility, and significantly reduces the QOL of women in social and reproductive activities. In endometriosis, menstrual pain is extremely frequent, and pain symptoms such as lower abdominal pain, lower back pain, sexual pain, and stool pain other than menstruation are also frequently observed.

  In endometriosis, many patients relapse or relapse until menopause unless radical surgery is performed, and long-term treatment and management are necessary. In the treatment of endometriosis, drug treatment is often the first choice. Drug therapy is divided into symptomatic treatment and endocrine therapy. Analgesics etc. are used mainly for the purpose of amelioration of the pain accompanying endometriosis as coping treatment. For endocrine therapy, low-dose estrogen-progestin preparations, dienogest, gonadotropin-releasing hormone (GnRH) agonists and the like are used for the purpose of suppressing estrogen-dependent endometrial proliferation in addition to improvement of pain.

  However, in 10% to 30% of endometriosis patients, analgesics are said to have no control over the pain associated with endometriosis. In addition, in the use of a low dose estrogen-progestin preparation, attention must be paid to thrombosis, liver dysfunction and the like. Dienogest has been reported to have a side effect of 71.9% of irregular genital hemorrhage in long-term administration trials, which may lead to severe anemia. As GnRH agonists may show a decrease in bone mineral density due to the estrogen-lowering effect, administration over 6 months is not accepted in principle.

  As described above, in the drug therapy for treatment of endometriosis, there are many patients in which continuous administration is difficult because the side effects specific to each drug are observed. Therefore, the development of new drugs that can reduce side effects and can be administered over a long period of time is desired.

  In the treatment of endometriosis, as a threshold value of blood estradiol (E2) which suppresses the growth of the endometriosis lesion and does not cause a serious reduction of bone mineral density based on the estrogen lowering action, etc. There is a concept called “therapeutic window” (Non-patent Document 1). For example, in Non-Patent Document 1, it is described that an E2 concentration of 30 to 50 pg / mL will be a therapeutic window. In addition, it has also been suggested that, when the E2 concentration is less than 20 pg / mL, the endometriosis lesion atrophy, but the bone mineral loss is remarkable.

3- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] -2,4-dioxo-1,2,3 represented by the following formula (I) Patent Document 1 describes 2,4-tetrahydrothieno [3,4-d] pyrimidine-5-carboxylic acid (hereinafter referred to as Compound 1). Also, Patent Document 2 describes a choline salt of Compound 1 (hereinafter referred to as Compound 2). In Patent Documents 1 and 2, a condensed heterocyclic derivative containing Compound 1 or Compound 2 has GnRH antagonism, prostatic hypertrophy, uterine fibroid, endometriosis, uterine fibroma, precocious pubertal onset, amenorrhea It is described that it can be used as a prophylactic or therapeutic agent for sex hormone dependent diseases such as premenstrual syndrome, dysmenorrhea and the like. Patent documents 1 and 2 also disclose that the orally administered agent can be prepared such that the fused heterocyclic derivative or compound 2 is administered in the range of 0.1 mg to 1000 mg.

  Patent documents 1 and 2 only describe the general pharmaceutical use of the fused heterocyclic derivative or the compound 2 containing the compound 1 based on GnRH antagonism and the description of the general dose. The dosage regimen of Compounds 1 and 2 for reducing the risk of lowering bone mineral density based on the estrogen lowering action and exerting an excellent therapeutic effect on endometriosis is not specifically described. .

WO 2007/046392 International Publication No. 2011/0099507

Robert L. Barbieri, "The Journal of Reproductive Medicine", 1998, volume 43, supplement, p. 287-292

  An object of the present invention is to provide a drug that reduces the risk of bone mineral loss based on the estrogen-lowering effect and exhibits excellent therapeutic effect on endometriosis.

  The inventors of the present invention conducted intensive studies to solve the above problems, and as a result, usage of compound 1 that reduces the risk of bone mineral loss due to the estrogen lowering action as well as the optimal balance of drug efficacy and side effects.・ I found a dose.

That is, the present invention relates to the following [1] to [5] and the like.
[1] 3- [2-Fluoro-5- (2, 3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [3 , 4-d] pyrimidine-5-carboxylic acid or a pharmacologically acceptable salt thereof, which is a pharmaceutical composition for treating endometriosis,
A pharmaceutical composition, which is orally administered at a daily dose of 50 mg to 75 mg of the above compound as a daily dose.
[2] The pharmacologically acceptable salt is 3- [2-fluoro-5- (2, 3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] -2,4-dioxo-1, The pharmaceutical composition according to [1] above, which is 2,3,4-tetrahydrothieno [3,4-d] pyrimidine-5-carboxylic acid / choline salt.
[3] The pharmaceutical composition according to [1] or [2] above, wherein the daily dose is 50 mg in terms of free form.
[4] The pharmaceutical composition according to [1] or [2] above, wherein the daily dose is 75 mg in terms of free form.
[5] The pharmaceutical composition according to any one of the above [1] to [4], which is for the treatment of endometriosis is for the treatment of pain associated with endometriosis.

In another embodiment, the present invention provides the compound of the present invention with a requisite amount of 3- [2-fluoro-5- (2, 3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] -2,4-dioxo-1 Endometriosis comprising administering to a patient a pharmaceutical composition comprising 2,2,3,4-tetrahydrothieno [3,4-d] pyrimidine-5-carboxylic acid or a pharmaceutically acceptable salt thereof Treatment method of
The present invention relates to a method of treatment comprising orally administering once daily a daily dose of 50 mg to 75 mg of the compound as a free body equivalent.

In another embodiment, the present invention provides 3- [2-fluoro-5- (2, 3-difluoro-6-methoxybenzyloxy)-for producing a pharmaceutical composition for treating endometriosis. Use of 4-methoxyphenyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidine-5-carboxylic acid or a pharmacologically acceptable salt thereof ,
The present invention relates to a use characterized in that 50 mg to 75 mg of the aforementioned compound is orally administered as a daily dose once a day, as a free body equivalent value.

  The pharmaceutical composition of the present invention reduces the risk of bone mineral loss due to the estrogen lowering action, and exerts an excellent therapeutic effect on endometriosis.

The NRS score of endometriosis patients is shown. The vertical axis represents the change in average NRS of pelvic pain (whether menstrual period or menstrual period) for pelvic pain from the pre-observation period. The horizontal axis indicates the measurement time. "Pre treatment" is the pre-observation period, "Week 4", "Week 8" and "Week 12" are the 4th, 8th and 12th weeks after the start of administration, and "End of Treatment" is the final evaluation of the treatment period I mean each time. In the figure, the black squares indicate the 50 mg dose group, the black triangles the 100 mg dose group, the black circles the 200 mg dose group, and the white squares the placebo group. The E2 concentration in the treatment phase of an endometriosis patient is shown. The vertical axis shows the median value of E2 concentration (pg / mL). The horizontal axis indicates the measurement time. “Pre treatment” indicates the pre-observation period, and “Week 4”, “Week 8” and “Week 12” indicate the fourth week, the eighth week and the twelfth week from the start of administration, respectively. In the figure, the black squares indicate the 50 mg dose group, the black triangles the 100 mg dose group, the black circles the 200 mg dose group, and the white squares the placebo group.

  Hereinafter, embodiments of the present invention will be described in more detail.

  In the present invention, each term has the following meaning, unless otherwise specified.

  In the present invention, compound 1 means “3- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] -2,4-dioxo-1,2,3 , 4-Tetrahydrothieno [3,4-d] pyrimidine-5-carboxylic acid], compound 2 is “3- [2-fluoro-5- (2, 3-difluoro-6-methoxybenzyloxy) -4-Methoxyphenyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidine-5-carboxylic acid / choline salt ". Compound 1 and “5-carboxy-3- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] thieno [3,4-] described in Patent Document 1 and Patent Document 1 d] Pyrimidin-2, 4 (1H, 3H) -dione "is the same compound.

  In the present invention, Compound 1 can also be converted into a pharmacologically acceptable salt thereof according to a conventional method, as needed. Examples of such salts include sodium salts; potassium salts; addition salts with organic bases such as N, N'-dibenzylethylenediamine, 2-aminoethanol, choline and the like, and the like. Preferably, the choline salt of compound 1 (compound 2) is mentioned.

  In the present invention, the “pharmaceutically acceptable salt of Compound 1” also includes solvates with pharmaceutically acceptable solvents such as water and ethanol.

  Compounds 1 and 2 of the present invention can be produced by known methods. For example, Compound 1 of the present invention can be produced by WO 2007/046392 (Patent Document 1), and Compound 2 can also be produced by the method described in WO 2011/099507 (Patent Document 2) or a method analogous thereto.

  The pharmaceutical composition of the present invention is used in various dosage forms depending on the usage. As such a dosage form, for example, orally administered agents such as powders, granules, fine granules, dry syrups, tablets, capsules and the like can be mentioned.

  The pharmaceutical composition of the present invention is prepared using Compound 1 or a pharmacologically acceptable salt thereof as an active ingredient, and at least one pharmaceutical additive. The pharmaceutical composition of the present invention can also be prepared by appropriately mixing, diluting or dissolving the pharmaceutical additive with a method known pharmaceutically in accordance with the dosage form. As such pharmaceutical additives, excipients such as lactose, lubricants such as magnesium stearate, disintegrants such as carboxymethylcellulose, binders such as hydroxypropyl methylcellulose, surfactants such as macrogol, hydrogen carbonate Examples thereof include foaming agents such as sodium, solubilizing agents such as cyclodextrin, acidulants such as citric acid, stabilizers such as sodium edetate, and pH adjusters such as phosphate.

  The pharmaceutical composition of the present invention is useful as a therapeutic agent for endometriosis, and has an improving effect on pain associated with endometriosis (pelvic pain, stool pain, pain at internal examination, etc.), endometriosis Or one or more of a reduction effect on ovary chocolate cysts, an improvement effect on objective findings (induration of Douglas fossa, and restriction of uterine mobility), a decrease in usage rate of an analgesic, and the like.

  In one embodiment, the pharmaceutical composition according to the present invention is endometriosis which is resistant to stopping menstruation because menstruation is maintained during the treatment of endometriosis according to the embodiment. It can also be used on patients.

  In the present invention, the daily dose for an adult of the active ingredient (compound 1 or a pharmacologically acceptable salt thereof) is 50 mg to 75 mg (compound 1 is a pharmacologically acceptable salt thereof) for oral administration. In some cases, it can be determined in the range of 50 mg to 75 mg as a free body equivalent value. For example, 50 mg or 75 mg of Compound 2 can be used as a first dose for free form conversion to adults, and 50 mg or 75 mg of Compound 2 can be orally administered as a free form conversion during the treatment period. Also, based on the patient's age, body weight, degree of disease, occurrence of side effects, etc., it can be used by appropriately increasing or decreasing in the range of 25 mg to 100 mg of Compound 2 as a free body equivalent value at the discretion of the doctor.

  The pharmaceutical composition of the present invention can also be administered, for example, from the first day to the fifth day of menstruation.

The dosage regimen of the pharmaceutical composition of the present invention includes, for example, a method of orally administering 50 mg or 75 mg of Compound 2 once a day as a daily dose as a daily dose.
In addition, according to the judgment of the doctor, the daily dose may be increased or decreased within the above range. Also, at the discretion of the physician, the daily dose may be divided into two or three doses.

  In the present invention, the "risk of reduction of bone mineral density based on the estrogen lowering action" means the risk of bone mineral density decrease accompanying the suppression of E2 secretion. The degree of "risk of reduction of bone mineral density based on the estrogen lowering action" by the pharmaceutical composition of the present invention depends on the E2 concentration or the appearance of hypoestrogen symptoms such as hot flashes, headache, floating dizziness and hyperhidrosis. It can also be evaluated.

  The pharmaceutical composition of the present invention can be adjusted to an appropriate E2 concentration that can reduce the risk of bone mineral loss due to the estrogen lowering action. The appropriate E2 concentration is preferably 20 pg / mL to 50 pg / mL, more preferably 30 pg / mL to 50 pg / mL in the treatment phase.

  The pharmaceutical composition of the present invention can reduce the side effects due to excessive secretion suppression of E2, for example, the onset of hypoestrogen symptoms such as hot flashes, headaches, dizziness and hyperhidrosis accompanying drug administration.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to the contents. In Examples, the dose (dose) of Compound 2 means a dose as a free form (free body equivalent value) unless otherwise specified.

Example 1
Clinical trial 1 for patients with endometriosis (double-blind, parallel-group comparative study)
1. Test method 50 mg (29 cases), 100 mg (26 cases) or 200 mg (28 cases) of Compound 2 or placebo (24 cases) once a day for 12 weeks after breakfast for 107 patients with endometriosis Each was orally administered. Hereinafter, the 50 mg administration group, the 100 mg administration group, the 200 mg administration group, and the placebo group are referred to, respectively. Medication was started from the second day to the fifth day of menstruation.

2. Efficacy and safety evaluation items NRS scores for menstruation or pelvic pain other than menstruation (0: no pain to 10: most severe pain experienced so far), menstrual time or month as evaluation items for efficacy Severity of pelvic pain except for time (0: no pain to 4: tolerable even with analgesics), temporary pain (pain pain, pain at internal examination and sexual pain), objective findings (Douglas's pits) Severity of induration and uterine mobility, rate of use of analgesics, size of ovarian chocolate cyst and uterus, endocrinology examination (E2, luteinizing hormone (LH), ovarian stimulating hormone (FSH) and progesterone ), And the presence or absence of menstruation.
As the safety-related evaluation items, the occurrence of adverse events, the occurrence of side effects, and genital bleeding were evaluated.

3. Results The change in the amount of change in the average NRS score (whether menstrual period or other than menstrual period) for pelvic pain is shown in FIG. The amount of change in the average NRS score (whether menstruation time or menstruation time) for pelvic pain at the time of final evaluation from treatment period to treatment period is 50 mg administration group, 100 mg administration group, 200 mg administration group, and placebo group in this order -1.13, -1.27, -1.33 and -0.19. Significant improvement was observed in all compound 2 administration groups as compared to the placebo group. In addition, temporary pain, objective findings, analgesic use rate, ovarian chocolate cyst and uterus size were also improved in the Compound 2 administration group as compared to the placebo group.
The incidence of side effects related to hypo-estrogen symptoms (hot flashes, headache, floating dizziness and hyperhidrosis) was 9 in total in the 50 mg group, 12 in 100 g group, 28 in 200 mg group, placebo group Was one case.
The transition of the median E2 concentration in the treatment period is shown in FIG. In all compound 2 administration groups, suppression of E2 secretion was observed. In addition, as a result of analyzing the occurrence of side effects (hot flashes, headache, dizziness and hyperhidrosis) associated with low estrogen symptoms for each concentration of E2 during the treatment period, the side effects were observed in the group with E2 concentration of 20 pg / mL or more While the expression rate was 28.2%, the incidence rate of side effects was 54.8% in the group of E2 concentration less than 20 pg / mL.
The presence or absence of menstruation in the treatment period is shown in Table 1. In the table, “Compound 2 50 mg” is 50 mg administration group, “Compound 2 100 mg” is 100 mg administration group, “Compound 2 200 mg” is 200 mg administration group, “Placebo” is placebo group, and “Yes” is menstruation observed during the treatment period. The percentage of patients who have been treated, and "No" mean the percentage of patients who did not have menses during the treatment period. As the dose decreased, the proportion of patients who had menstruation during the treatment phase increased.

From the results of Example 1, the 50 mg administration group shows an effect similar to the 100 mg administration group and the 200 mg administration group in the therapeutic effect on the pain associated with endometriosis, and the risk of bone mineral density reduction based on the estrogen lowering action Was shown to be reduced.
On the other hand, although the 100 mg and 200 mg administration groups showed a sufficient effect in treating the pain associated with endometriosis, the incidence of side effects of low estrogen symptoms is high, and the concentration of E2 during the treatment period is 20 pg / It fell below mL.
In addition, it was shown that the side effect of the low estrogen symptom is reduced in the group where the concentration of E2 in the treatment period is 20 pg / mL or more compared to the group less than 20 pg / mL.

Example 2
Clinical trial 2 for patients with endometriosis (randomized, open-label, parallel-group comparative study)
1. Test method Compound 21 of 75 mg (11 cases) or 150 mg (10 cases) was orally administered once a day once after breakfast for 8 weeks for 21 endometriosis patients. Hereinafter, each is referred to as a 75 mg administration group and a 150 mg administration group. Medication was started from the second day to the fifth day of menstruation.

2. Evaluation Items Regarding Efficacy and Safety The same items as Example 1 were evaluated as evaluation items regarding efficacy and safety.

3. Results The change in the average NRS score (whether menstruation or menstruation) for pelvic pain at the time of final observation from the observation period is -0.94 and -1.68 in the order of 75 mg administration group and 150 mg administration group. Met. A tendency to improve was observed in all Compound 2 administration groups.
The median E2 concentration in the treatment phase was 35 pg / mL and 10 pg / mL at 4 weeks and 24 pg / mL and 10 pg / mL at 8 weeks in the order of 75 mg dose group and 150 mg dose group.

  From the results of Example 2, the 75 mg dose group also shows an effect similar to the 100 mg dose group and the 200 mg dose group in the therapeutic effect on the pain associated with endometriosis, and the risk of bone mineral amount reduction based on the estrogen lowering action It has been shown that the

Example 3
Clinical trial 3 for patients with endometriosis (randomized double-blind parallel group comparison study)
1. Test Method To target 400 endometriosis patients, 25 mg, 50 mg, 75 mg or 100 mg of Compound 2 or placebo is orally administered once daily and after breakfast for 12 weeks. Dosing is started from the first day to the fifth day of menstruation.
2. Efficacy and safety evaluation items NRS scores for menstruation or pelvic pain other than menstruation (0: no pain to 10: most severe pain experienced so far), menstrual time or month as evaluation items for efficacy Severity of pelvic pain except for time (0: no pain to 4: tolerable even with analgesics), temporary pain (pain pain, pain at internal examination and sexual pain), objective findings (Douglas's pits) Severity of induration and uterine mobility, size of ovarian chocolate cyst and uterus, quality of life (Endometriosis Health Profile-30 (EHP-30)), usage rate of analgesics, endocrinological examination (E2, lupus) To assess the presence of forming hormone (LH), ovarian stimulating hormone (FSH) and progesterone), menstruation, etc.
Evaluation items related to safety include adverse events, adverse reactions, genital hemorrhage, bone metabolism markers (serum type I collagen cross-linked N-telopeptide (serum NTX) and bone alkaline phosphatase (BAP)), bone density Evaluate (by the DXA method) etc.

  From the results of Examples 1 and 2, by orally administering 50 mg to 75 mg of Compound 2 in a daily dose once a day as a daily dose, the risk of bone mineral level reduction based on the estrogen lowering action is reduced. It has been shown to exert an excellent therapeutic effect on endometriosis.

The pharmaceutical composition of the present invention is extremely useful as a therapeutic agent for endometriosis.

Claims (5)

3- [2-fluoro-5- (2, 3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4- d) A pharmaceutical composition for treating endometriosis, which comprises pyrimidine-5-carboxylic acid or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is orally administered at a daily dose of 50 mg to 75 mg of the above compound as a daily dose. The pharmacologically acceptable salt is 3- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] -2,4-dioxo-1,2,3. The pharmaceutical composition according to claim 1, which is 2,4-tetrahydrothieno [3,4-d] pyrimidine-5-carboxylic acid choline salt. The pharmaceutical composition according to claim 1 or 2, wherein the daily dose is 50 mg in terms of free body. The pharmaceutical composition according to claim 1 or 2, wherein the daily dose is 75 mg in terms of free body. The pharmaceutical composition according to any one of claims 1 to 4, wherein the treatment of endometriosis is for the treatment of pain associated with endometriosis.

Images